KR20120023754A - Antitumor combination including ave8062 and sorafenib - Google Patents

Abstract

의 AVE8062

The present invention relates to pharmaceutical anti-tumor combinations comprising AVE8062 of Formula (I) and Sorafenib of Formula (II), wherein both of the anti-tumor agents may be in base or pharmaceutically acceptable acid salt form.
Chemical formula

AVE8062

Description

ANTITUMOR COMBINATION INCLUDING AVE8062 AND SORAFENIB}

The present invention relates to antitumor combinations combining AVE8062 and sorafenib, which are effective in the treatment of cancer, more particularly solid tumors.

WO 2007/077309 describes a combination of anti-angiogenic agent AVE8062 (or VDA, vascular blocker) and anti-angiogenic VEGF traps.

WO 99910779 describes AVE8062 / platinum salt combinations.

WO 2004/037258 discloses taxanes (taxols, taxotels), alkylating agents (cyclophosphamides, ifosfamides, etc.), anti-metabolites (5-FU, cytarabine, etc.), epipodophyllotoxins, antibiotics (doxorubicin, etc.). And combinations of AVE8062 with various anti-tumor agents selected from vinca alkaloids.

EP 1407784 describes the AVE8062 / dexamethasone combination.

On the website www.clinicaltrials.gov, a patient recruiter for phase I studies of the combretastatin CA4P / Avastin combination (“increase of combretastatin in combination with bevacizumab (avastin) in patients with progressive solid tumors Safety studies of the dose ") are described. Excluded patients are designated patients who have already received treatment based on VEGF or VEGFR inhibitors, such as sorafenib or sutents (“Exclusion criteria: CA4P or Bevacizumab, or Vascular Endothelial Growth Factor (VEGF) or VEGFR signaling. Prior therapy with other agents, such as sorafenib and sutent. ").

In the file for Nexava available on the EMEA website (http://www.emea.europa.eu/humandocs/PDFs/EPAR/nexavar/H-690-PI-fr.pdf), Nexava ^? Rate) can be combined with various anticancer agents such as gemcitabine, oxaliplatin, doxorubicin, irinotecan or docetaxel.

Brief description of the invention

The present invention is formula:

의 AVE8062 및 화학식:

AVE8062 and chemical formula:

의 소라페닙을 포함하는 항종양 제약 조합물에 관한 것이며, 여기서 이들 2종의 항종양제는 염기 형태 또는 제약상 허용되는 산의 염 형태로 존재할 수 있다. 조합물은 유효량의 AVE8062 및 유효량의 소라페닙을 포함한다.

An anti-tumor pharmaceutical combination comprising sorafenib, wherein these two anti-tumor agents may be present in base form or in salt form of a pharmaceutically acceptable acid. Combinations include an effective amount of AVE8062 and an effective amount of sorafenib.

The combination is for administration to a patient during a cycle comprising administration of AVE8062 and several doses of sorafenib, which marks the beginning of the cycle, wherein the combination is administered at staggered time and is not administered simultaneously, It is administered prior to the very first dose of sorafenib. AVE8062 may be administered on the same day as sorafenib with a time delay of 1 to 4 hours prior to the very first dose of sorafenib. AVE8062 can also be administered the day before the very first dose of sorafenib, more particularly with a time delay of 24 hours or more. The cycle is repeated and the interval between two doses of AVE8062 ranges from 1 to 4 weeks.

The invention also relates to the use of AVE8062 and sorafenib for the preparation of the antitumor combinations described above.

[Description of Invention]

Justice

? Pharmaceutically acceptable acids: organic or inorganic acids with low toxicity (see "Pharmaceutical salts" J. Pharm. Sci. 1977, 66, 1-19);

? Effective amount: The amount of pharmaceutical compound that produces an effect on the tumor to be treated.

Regarding AVE8062, it belongs to the combretastatin family and has the formula:

(This is the Z isomer)

It is an antivascular agent (or VDA, angioblocker). It has the chemical name: (Z) -N- [2-methoxy-5- [2- (3,4,5-trimethoxyphenyl) vinyl] phenyl] -L-serinamide. This compound described in EP 731085 B1 can be prepared according to the method described in WO 03/084919. AVE8062 can be administered in the form of a base (see formula above) or in the form of a salt of a pharmaceutically acceptable acid, for example the hydrochloride form indicated below:

AVE8062, when administered, releases in vivo an active metabolite (Z) -1- (3-amino-4-methoxyphenyl) -2- (3,4,5-trimethoxyphenyl) ethene having the formula :

It is therefore also possible to replace AVE8062 with another combretastatin (base form or salt form of a pharmaceutically acceptable acid) of the formula which releases the metabolite in vivo:

Wherein Y represents an amino acid.

About Sora penip, which is marketed by Bayer HealthCare (Bayer HealthCare) under the trade name ^Nexavar? Sorafenib has the following chemical formula: 4- [4-[[4-chloro-3- (trifluoromethyl) phenyl] carbamoylamino] phenoxy] -N-methylpyridine-2-carboxamide Is a multikinase inhibitor that targets VEGF and BRAF receptors:

It is an antiangiogenic agent. This compound is described in WO 00/42012 and WO 00/41698. Sorafenib can be administered in the form of a base (see formula above) or in the form of a salt of a pharmaceutically acceptable acid, for example tosylate.

With regard to the combination, it consists of the combination of AVE8062 and sorafenib in the form of two separate pharmaceutical formulations.

The combination is administered repeatedly over several cycles according to the protocol depending on the nature and stage of the cancer to be treated and also the patient to be treated (age, weight, previous treatment (s), etc.). Each cycle begins with the administration of AVE8062, in addition to several administrations of sorafenib (hence one cycle is characterized by the administration of AVE8062 and several administrations of sorafenib, marking the beginning of the cycle). AVE8062 is administered to a patient in an interstitial pattern at intervals between two doses (duration of one cycle) that can range from 1 to 4 weeks, for example 3 weeks (Comment: for the test on mice, of AVE8062 Dosing interval was 4 or 5 days). Sorafenib may itself be administered to a patient in a daily pattern over a specific duration of the cycle. Sorafenib may be optionally administered until the end of one cycle.

The mode of administration may be parenteral and / or oral, and depends on the use of the herbal form for antitumor agents. By the parenteral route, the anti-tumor agent can be administered intravenously as a bolus or made into an intravenous infusion bag with pharmaceutically acceptable vectors by various methods known to those skilled in the art. According to one particular manner, AVE8062 is administered parenterally, such as via intravenous administration, as a bolus or via infusion, and sorafenib is administered orally.

One herbal form of AVE8062 suitable for parenteral administration is that AVE8062 is a solution in water. A galenical form of a seashell penip suitable for oral administration include, for example, in the form as marketed under the trade name Nexavar tablet ^form? Containing seashell penip tosylate in the form of a seashell penip 274 mg (200 mg active ingredient being equivalent).

The dose of AVE8062 and sorafenib administered to the patient each time depends on various parameters such as the nature and stage of the cancer to be treated and also the patient to be treated (age, weight, previous treatment (s), etc.). AVE8062 can be administered at an acceptable dose of 5 to 100, 5 to 60, 10 to 50, 20 to 42, or 20 to 40 mg / m 2 (weight / body surface area, dose defined for each administration). Sorafenib may be administered at an acceptable dose of 200 to 600 mg, or 300 to 500 mg (the dose defined for each administration) per se. Sorafenib can be taken twice daily at a dose of 200 mg of active ingredient, which corresponds to a daily dose of 400 mg. In addition, according to product instructions, it is recommended that the product be taken at least 1 hour before or 2 hours after meals.

The combination is effective in the treatment of cancer, more particularly solid tumors, in general, more particularly sarcomas, lung cancers, ovarian cancers, kidney cancers or liver cancers.

It has been observed that two antitumor agents are staggered and not administered simultaneously over a period of time, and better efficacy of tumor treatment is obtained when AVE8062 is administered just before the first dose of sorafenib. It became.

According to one particular manner, AVE8062 is administered on the same day as sorafenib with a time delay of 1 to 4 hours before the very first dose of sorafenib. Cycle example: Day D1: infusion of AVE8062, and oral administration of sorafenib 1-4 hours post-infusion (eg, in the form of sorafenib 2 doses); Days D2 to D14: Following oral administration of sorafenib (eg in the form of sorafenib 2 doses), the cycle is repeated at D1 +3 weeks.

According to another particular manner, AVE8062 is administered the day before the first dose of sorafenib. More particularly, the time delay between the administration of AVE8062 and the very first administration of sorafenib is at least 24 hours. Example cycle: D1 day: injection of AVE8062; Day D2 after a time delay of at least 24 hours: oral administration of sorafenib (eg, in the form of 2 doses of sorafenib); Days D3 to D14: Following oral administration of sorafenib (eg in the form of sorafenib 2 doses), the cycle is repeated at D1 +3 weeks.

The efficacy of the combination can be demonstrated by determining its therapeutic synergy. The combination shows therapeutic synergism when it is therapeutically superior to the best agent used alone at its optimal dose (TH Corbett et al., Cancer Treatment Reports 1982, 66, 1187). The efficacy of the combination can also be demonstrated by comparing the maximum tolerated dose of the individual with the maximum tolerated dose of each individual component in the study. This efficacy can be quantified by log ₁₀ cell killing, determined by the formula:

log ₁₀ cell death = TC (day) /3.32 × T _d

Where TC is the tumor growth delay (days), which is the average time required for the treatment tumor (T) to reach a predetermined value (eg 1 g) and the time required for the control tumor (C) to reach the same value. T _d represents the time, in days, required to double the volume of the control tumor during the exponential phase of tumor growth (TH Corbett et al. Cancer, 1977, 40, 2660-2680); FM Schabel et al. , Cancer Drug Development, Part B, Methods in Cancer Research 1979, 17, 3-51, New York, Academic Press Inc.]. If log ₁₀ cell death is greater than or equal to 0.7 the product is considered active. If log ₁₀ is greater than 2.8, the product is considered highly active. If the treatment time is at least 10 days and / or differs between the two agents evaluated in the combination, net log cell death can be calculated:

Net log ₁₀ cell death = (TC (day))-(treatment time (days)) / 3.32 x T _d .

In this case activity is acknowledged for net log cell death that is positive (> 0). Cytostatic inhibition activity corresponds to zero log cell death, i.e. treatment time equals duration of antitumor effect.

The combination is best used when log ₁₀ cell killing is best administered when the best component is administered alone, when each component is used at its own maximum allowable dose, which is generally present in a dose that does not exceed its maximum allowable dose. A therapeutic synergism will be indicated if it is at least 1 log ₁₀ greater than the value of the component's log ₁₀ cell death.

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Antitumor Effects and Tests

The efficacy of the combination on solid tumors could be determined experimentally in the following way: Animals of the subjects were subcutaneously bilaterally on day 0 with fragments of 30 to 60 mg of NCI-H460 (ATCC # HTB-177) human non-small cell lung tumors on day 0 Transplanted female SCID mice. For early tumor treatment, animals were randomly distributed into various groups, either the group intended to receive treatment (s) or the group intended to receive no treatment (s) (control). If in doubt about the treatment of advanced tumors, animals with tumors that exceeded a predefined tumor size of more than 150 mg were distributed to various treatment and control groups in a way that the tumor size range was comparable from one group to the other. . In order to be able to separate toxic effects from specific effects on tumors, animals without tumors could also be treated with the same treatments as animals with tumors. In general, chemotherapy was initiated 3 to 22 days after transplantation, depending on the type of tumor and the desired tumor size. Animals were observed daily and weighed. Doses that induce at least 20% weight loss or at least 10% mortality at the lowest point (mean of the group) were considered toxic. Tumor activity was assessed at the highest non-toxic dose or at the highest test dose with respect to acytotoxic agents.

Tumors were measured twice or three times per week until the tumors reached approximately 2 g or if the animals died before the tumors reached 2 g. Necropsy was done when the animals were sacrificed.

Antitumor activity was determined according to various recorded parameters such as dose (mg / kg), method of administration, time of administration, toxicity, and delayed tumor growth and also log ₁₀ cell killing depending on time of tumor doubling.

In connection with the following study, AVE8062 (hydrochloride form) was formulated in 0.9% NaCl in water. Sorafenib was formulated with 12.5% ethanol, 12.5% polysorbate 80 and 75% 5% glucose in water.

Study 1: Sorafenib administered concurrently with AVE8062 (Table 1)

AVE8062 was administered intravenously on days 9 and 13 after tumor transplantation. Sorafenib was administered orally on days 9-24. When two agents were administered in combination, the same schedule as the agents alone was used, and the combination of the two agents was performed simultaneously on the 9th and 13th days.

Tumor doubling time was 2 days.

Median tumor weight at initiation of treatment was 219-234 mg, and when the control group reached a tumor weight of 1000 mg, it was 12.8 days after tumor transplantation.

The highest rated dose (HED) of AVE8062 was 58 mg / kg per injection, ie a total dose of 116 mg / kg. At this dose, AVE8062 was active with 0.9 log ₁₀ cell killing (log cell killing) with 1/6 partial regression (PR = 50% regression of initial tumor size).

Sorafenib was active with 2.3 log cell killing at the highest test dose (HDT) of 62 mg / kg per dose, ie at a total dose of 992 mg / kg. However, sorafenib did not have cytostatic activity at this dose (-0.1 net log cell death) and the tumor was out of treatment.

The highest nontoxic dose of the combination (HNTD) was determined at the dose of 36 mg / kg per dose of AVE8062 in combination with the dose of 62 mg / kg per dose of sorafenib, and the higher dose of the combination was found to be toxic. In this HNTD, the combination was active with 2.4 log cell kill and 0.0 net log cell kill. However, no partial regression was observed at this dose. Lower doses of the combination were also active without inducing tumor regression (2.2 to 2.5 log cell death).

In conclusion, simultaneous administration of AVE8062 and sorafenib was active and maintained above the therapeutic benefit of each of the two agents alone. In addition, it was observed that this activity was maintained at various dose levels only for the combination.

Study 2: Sorafenib administered 1 hour after AVE8062 in combination (Table 2)

AVE8062 was administered intravenously on days 10 and 14 after tumor transplantation. Sorafenib was administered orally on days 10-14. The two agents were administered in combination according to the same schedule as the agents alone, except that sorafenib was staggered 1 hour after the administration of AVE8062.

Tumor doubling time was 1.6 days.

The median tumor weight at the start of treatment was 431-458 mg, and the time point when the control group reached the tumor weight of 1500 mg was 13.2 days after tumor implantation.

The two highest doses of AVE8062 were toxic and the highest nontoxic dose (HNTD) was 22.3 mg / kg per injection, ie a total dose of 44.6 mg / kg. At this dose, AVE8062 was active with 1.1 log ₁₀ cell death (log cell death) without inducing tumor regression.

Sorafenib was also active at 1.1 log cell killing at the highest test dose (HDT) of 100 mg / kg per dose, ie at a total dose of 447.4 mg / kg.

The HNTD of the combination was determined at a dose of 58 mg / kg per dose of AVE8062 in combination with a dose of 38.4 mg / kg per dose of sorafenib, and the higher dose of the combination was found to be toxic. In this HNTD, the combination was active with 2.1 log cell killing, 1 log cell killing greater cell killing than agent alone (1.1 log cell killing for each). In addition, 50% (3/6) of partial regression (PR = 50% regression of initial tumor size) was observed at this dose. Five lower doses of the combination were also active with log cell killing of 1.9 to 1.5 and induced PR at 4 dose levels.

In conclusion, the combination of sorafenib and AVE8062 administered 1 hour later induced greater tumor regression than each of the agents alone, and a therapeutic synergy was observed in HNTD.

Study 3: Sorafenib administered 24 hours after AVE8062 in combination (Table 3)

Female SCID mice were administered AVE8062 intravenously on days 9 and 14 after transplantation of NCI-H460 lung tumors. Sorafenib was administered orally on days 9-20. When two agents were administered in combination, the same schedule as the agents alone was used, but the administration of sorafenib was started 24 hours after the administration of AVE8062.

Tumor doubling time was 1.5 days.

The median tumor weight at the start of treatment was 217-235 mg, and the time point when the control group reached a tumor weight of 1000 mg was 13.6 hours after tumor transplantation.

The highest nontoxic dose (HNTD) of AVE8062 was 36 mg / kg per injection, ie a total dose of 72 mg / kg. At this dose, AVE8062 was active with 1.7 log ₁₀ cell death (log cell death) without inducing tumor regression.

Sorafenib was also active with 2.4 log cell killing at the highest test dose (HDT) of 100 mg / kg per dose, ie at a total dose of 1213.3 mg / kg. However, sorafenib did not have cytostatic activity at this dose (-0.4 net log cell death) and the tumor was out of treatment.

The HNTD of the combination was determined at a dose of 36 mg / kg per dose of AVE8062 in combination with a dose of 100 mg / kg per dose of sorafenib, and the higher dose of the combination was found to be toxic. In this HNTD, the combination was highly active with 3.1 log cell kill and 0.3 net log cell kill. In addition, at this dose 50% (3/6) of partial regression (PR = 50% regression of initial tumor size) and 16% (1/6) of complete regression (CR = 63 mg below the detectable limit) Got. Lower doses of the combination were also active (2.6-3 log cell killing) and induced PR at five dose levels and CR at two dose levels.

In conclusion, this combination using the order of administering sorafenib after AVE8062 induced complete and / or partial tumor regression, which was not observed with the agent alone. These degenerations were observed at various dose levels in the combination. Log ₁₀ cell killing in the combination was always higher than that observed in monotherapy.

In conclusion, in these three studies, staggered administration of sorafenib for at least 1 hour after administration of AVE8062 provides a therapeutic benefit compared to the administration of two antitumor agents alone. Increasing this interval up to at least 24 hours increases this therapeutic benefit.

Tumor doubling time = 2 days. Median Tumor Weight at Initiation of Treatment = 219-234 mg. Median time to reach 1000 mg in the control group = 12.8 days. Treatment time: Sorafenib = 16 days, AVE8062 = 5 days.

Formulation: AVE8062 in water with 0.9% NaCl; Sorafenib = 12.5% ethanol in water, 12.5% PS80, 75% 5% glucose.

Abbreviations: HED = highest rated dose, HNTD = highest non-toxic dose, HDT = highest test dose, PR = partial regression, CR = complete regression.

Tumor doubling time = 1.6 days. Median tumor weight at the start of treatment = 431-458 mg. Median time to reach 1500 mg in the control group = 13.2 days.

Formulation: AVE8062 with 0.9% NaCl; Sorafenib = 12.5% ethanol in water, 12.5% PS80, 75% 5% glucose.

Abbreviations: HNTD = highest nontoxic dose, HDT = highest test dose, BWC = weight change.

Tumor doubling time = 1.5 days. Median tumor weight at the start of treatment = 217-235 mg. Median time to reach 1000 mg in the control group = 13.6 days. Treatment time: combination and sorafenib alone = 12 days, AVE8062 alone = 5 days.

Formulation: AVE8062 with 0.9% NaCl; Sorafenib = 12.5% ethanol in water, 12.5% PS80, 75% 5% glucose.

Abbreviations: HNTD = highest nontoxic dose, HDT = highest test dose, PR = partial regression, CR = complete regression.

Claims (11)

Formula is an anti-tumor agent, which may exist in base form or in salt form of a pharmaceutically acceptable acid:

AVE8062 and chemical formula:

An anti-tumor pharmaceutical combination comprising sorafenib. The combination of claim 1, comprising an effective amount of AVE8062 and an effective amount of sorafenib. The combination according to claim 1 or 2, wherein AVE8062 is in hydrochloride form and / or sorafenib is in tosylate form. The start of a cycle according to any one of claims 1 to 3, characterized in that AVE8062 is administered prior to the very first administration of sorafenib, rather than being administered at staggered and concurrently over time. A combination for administration to a patient during a cycle comprising administration of AVE8062 and multiple administrations of sorafenib. The combination of claim 4, wherein AVE8062 is administered on the same day as sorafenib with a time delay of 1 to 4 hours prior to the very first dose of sorafenib. The combination of claim 4, wherein AVE8062 is administered the day before the very first administration of sorafenib. The combination of claim 6, wherein the time delay between administration of AVE8062 and the very first administration of sorafenib is at least 24 hours. The combination according to claim 4, wherein the cycle is repeated and the interval between two administrations of AVE8062 is in the range of 1 to 4 weeks. The combination of any one of claims 1 to 8, wherein AVE8062 is administered parenterally and / or sorafenib is administered orally. 10. The combination according to claim 1, for the treatment of solid tumors, more particularly sarcomas, lung cancers, ovarian cancers, kidney cancers or liver cancers. Use of AVE8062 and sorafenib for the preparation of an anti-tumor combination as described in any one of claims 1 to 10.